High sensitivity and amenability to miniaturization for field-portable applications have helped to make ion mobility spectrometry (IMS) an important technique for the detection of many compounds, including narcotics, explosives, and chemical warfare agents as described, for example, by G. Eiceman and Z. Karpas in their book entitled “Ion Mobility Spectrometry” (CRC, Boca Raton, 1994), the contents of which are incorporated by reference herein. In IMS, gas-phase ion mobilities are determined using a drift tube with a constant electric field. Ions are separated in the drift tube on the basis of differences in their drift velocities. At low electric field strength, for example 200 V/cm, the drift velocity of an ion is proportional to the applied electric field strength, and the mobility, K, which is determined from experimentation, is independent of the applied electric field. Additionally, in IMS the ions travel through a bath gas that is at sufficiently high pressure that the ions rapidly reach constant velocity when driven by the force of an electric field that is constant both in time and location. This is to be clearly distinguished from those techniques, most of which are related to mass spectrometry, in which the gas pressure is sufficiently low that, if under the influence of a constant electric field, the ions continue to accelerate.
E. A. Mason and E. W. McDaniel in their book entitled “Transport Properties of Ions in Gases” (Wiley, New York, 1988), the contents of which are incorporated by reference herein, teach that at high electric field strength, for instance fields stronger than approximately 5,000 V/cm, the ion drift velocity is no longer directly proportional to the applied electric field, and K is better represented by KH, a non-constant high field mobility term. The dependence of KH on the applied electric field has been the basis for the development of high field asymmetric waveform ion mobility spectrometry (FAIMS). Ions are separated in a FAIMS analyzer on the basis of a difference in the mobility of an ion at high field strength, KH, relative to the mobility of the ion at low field strength, K. In other words, the ions are separated due to the compound dependent behavior of KH as a function of the applied electric field strength.
In general, a device for separating ions according to the FAIMS principle has an analyzer region that is defined by a space between first and second spaced-apart electrodes. The first electrode is maintained at a selected dc voltage, often at ground potential, while the second electrode has an asymmetric waveform V(t) applied to it. The asymmetric waveform V(t) is composed of a repeating pattern including a high voltage component, VH, lasting for a short period of time tH and a lower voltage component, VL, of opposite polarity, lasting a longer period of time tL. The waveform is synthesized such that the integrated voltage-time product, and thus the field-time product, applied to the second electrode during each complete cycle of the waveform is zero, for instance VHtH+VLtL=0; for example +2000 V for 10 μs (microseconds) followed by −1000 V for 20 μs. The peak voltage during the shorter, high voltage portion of the waveform is called the “dispersion voltage” or DV, which is identically referred to as the applied asymmetric waveform voltage.
Generally, the ions that are to be separated are entrained in a stream of gas flowing through the FAIMS analyzer region, for example between a pair of horizontally oriented, spaced-apart electrodes. Accordingly, the net motion of an ion within the analyzer region is the sum of a horizontal x-axis component due to the stream of gas and a transverse y-axis component due to the applied electric field. During the high voltage portion of the waveform an ion moves with a y-axis velocity component given by vH=KHEH, where EH is the applied field, and KH is the high field ion mobility under operating electric field, pressure and temperature conditions. The distance traveled by the ion during the high voltage portion of the waveform is given by dH=vHtH=KHEHtH, where tH is the time period of the applied high voltage. During the longer duration, opposite polarity, low voltage portion of the asymmetric waveform, the y-axis velocity component of the ion is vL=KEL, where K is the low field ion mobility under operating pressure and temperature conditions. The distance traveled is dL=vLtL=KELtL. Since the asymmetric waveform ensures that (VHtH)+(VLtL)=0, the field-time products EHtH and ELtL are equal in magnitude. Thus, if KH and K are identical, dH and dL are equal, and the ion is returned to its original position along the y-axis on the completion of one cycle of the waveform. If at EH the mobility KH≠K, the ion experiences a net displacement from its original position relative to the y-axis. For example, if KH>K, a positive ion travels farther during the positive portion of the waveform, for instance dH>dL. Then the ion migrates away from the second electrode and eventually will be neutralized at the first electrode.
In order to reverse the transverse drift of the positive ion in the above example, a constant negative de voltage is applied to the second electrode. The difference between the dc voltage that is applied to the first electrode and the dc voltage that is applied to the second electrode is called the “compensation voltage” (CV). The CV voltage prevents the ion from migrating toward either the second or the first electrode. If ions derived from two compounds respond differently to the applied high strength electric fields, the ratio of KH to K may be different for each compound. Consequently, the magnitude of the CV that is necessary to prevent the drift of the ion toward either electrode is also different for each compound. Thus, when a mixture including several species of ions, each with a unique KH/K ratio, is being analyzed by FAIMS, only one species of ion is selectively transmitted to a detector for a given combination of CV and DV. In one type of FAIMS experiment, the applied CV is scanned with time, for instance the CV is slowly ramped or optionally the CV is stepped from one voltage to a next voltage, and a resulting intensity of transmitted ions is measured. In this way a CV spectrum showing the total ion current as a function of CV, is obtained.
Guevremont et al. have described the use of curved electrode bodies, for instance inner and outer cylindrical electrodes, for producing a two-dimensional atmospheric pressure ion focusing effect that results in higher ion transmission efficiencies than can be obtained using, for example, a FAIMS device having parallel plate electrodes. In particular, with the application of an appropriate combination of DV and CV an ion of interest is focused into a band-like region in the annular gap between the cylindrical electrodes as a result of the electric fields, which change with radial distance. Focusing the ions of interest has the effect of reducing the number of ions of interest that are lost as a result of the ion suffering a collision with one of the inner and outer electrodes. FAIMS devices with cylindrical electrode geometry have been described in the prior art, as for example in U.S. Pat. No. 5,420,424, issued May 30, 1995 in the name of Carnahan et al., the contents of which are incorporated by reference herein.
In WO 00/08455, filed on Aug. 5, 1999, and in U.S. Pat. No. 6,504,149, issued Jan. 7, 2003, the contents of both of which are incorporated by reference herein, Guevremont and Purves describe a domed-FAIMS analyzer. In particular, the domed-FAIMS analyzer includes a cylindrical inner electrode having a curved surface terminus proximate an ion outlet orifice of the FAIMS analyzer region. The curved surface terminus is substantially continuous with the cylindrical shape of the inner electrode and is aligned co-axially with the ion outlet orifice. During use, the application of an asymmetric waveform to the inner electrode results in the normal ion-focusing behavior as described above, and in addition the ion-focusing action extends around the generally spherically shaped terminus of the inner electrode. This causes the selectively transmitted ions to be directed generally radially inwardly within the region that is proximate the terminus of the inner electrode. Several contradictory forces are acting on the ions in this region near the terminus of the inner electrode. The force of the carrier gas flow tends to influence the ions to travel towards the ion-outlet orifice, which advantageously also prevents the ions from migrating in a reverse direction, back towards the ion source. Additionally, the ions that get too close to the inner electrode are pushed back away from the inner electrode, and those near the outer electrode migrate back towards the inner electrode, due to the focusing action of the applied electric fields. When all forces acting upon the ions are balanced, the ions are effectively captured in every direction, either by forces of the flowing gas, or by the focusing effect of the electric fields of the FAIMS mechanism. This is an example of a three-dimensional atmospheric pressure ion trap, as described in greater detail by Guevremont and Purves in U.S. Pat. No. 6,621,007, issued on Sep. 16, 2003, the contents of which are incorporated by reference herein.
Guevremont and Purves further disclose a near-trapping mode of operation for the above-mentioned domed-FAIMS analyzer, which achieves ion transmission from the domed-FAIMS to a mass spectrometer with high efficiency. Under near-trapping conditions, the ions that accumulate in the three-dimensional region of space near the spherical terminus of the inner electrode are caused to leak from this region, being pulled by a flow of gas towards the ion-outlet orifice. The ions that are extracted from this region do so as a narrow, approximately collimated beam, which is pulled by the gas flow through the ion-outlet orifice and into a small orifice leading into the vacuum system of the mass spectrometer. Accordingly, a tandem domed-FAIMS/MS device is a highly sensitive instrument that is capable of detecting and identifying ions of interest at part-per-billion levels.
More recently, in WO 01/69216 the contents of which are incorporated by reference herein, Guevremont and Purves describe a so-called “perpendicular-gas-flow-FAIMS”, which is identically referred to as a side-to-side FAIMS. The analyzer region of the side-to-side FAIMS is defined by an annular space between inner and outer cylindrical electrodes. In particular, ions that are introduced into the analyzer region of the side-to-side FAIMS are selectively transmitted in a direction that is generally around the circumference of the inner electrode. For instance, the ion inlet and the ion outlet of a side-to-side FAIMS device are disposed, one opposing the other, within a surface of the outer electrode such that ions are selectively transmitted through the curved analyzer region between the ion inlet and the ion outlet along a continuously curving ion flow path absent a portion having a substantially linear component. In particular, the ions travel from the ion inlet to the ion outlet by flowing around the inner electrode in one of a “clock-wise” and a “counter clock-wise” direction. This is in contrast to the above-mentioned FAIMS devices in which the ions are selectively transmitted along the length of the inner electrode.
Advantageously, the side-to-side FAIMS device reduces the minimum distance that must be traveled by the ions within the analyzer region to approximately fifty per cent of the circumference of the inner electrode. Since the ions split into two streams traveling in opposite directions around the inner electrode after they are introduced through the ion inlet, the effective ion density within the analyzer region is reduced, and so too is the ion-ion repulsion space charge effect reduced. Furthermore, the reduction of the minimum ion travel distance has the added benefit of improving the ion transmission efficiency. For example, by keeping the time for travel short, the effect of diffusion and ion-ion repulsion forces are minimized. In keeping distances short, the transit time of the ions through the analyzer region is also short, which supports more rapid analysis of ion mixtures.
Of course, there are various drawbacks associated with state of the art side-to-side FAIMS devices, particularly relating to the efficient utilization of a FAIMS analyzer. The down time of a FAIMS analyzer often is determined not by limitations of the FAIMS device itself, but by the specifics of an ion source, or by requirements due to sample preparation. Additionally, Tandem-FAIMS devices comprising two FAIMS analyzers are known in the prior art; however, while ions are being accumulated in a first, trapping FAIMS analyzer, before being released to the second, continuous FAIMS analyzer, the second continuous FAIMS analyzer is “idling,” and thus is not being fully utilized. It would therefore be highly advantageous to provide an apparatus that overcomes this problem of the prior art. For instance, a FAIMS analyzer that is in communication with a plurality of ion sources would allow for a more efficient utilization of the FAIMS analyzer. Advantageously, each ion source of the plurality of ion sources could be an embodiment of a different ionization technique. This would provide for an advanced method for optimizing ionization conditions for an unknown sample.
Furthermore, in conventional operation, a mass spectrometer is limited to one inlet aperture (orifice), due to limitations of pumping speed of the vacuum pumps that are connected to the low-pressure chamber, and because of the requirements of the ion optical components after the inlet aperture. It is a disadvantage that, in many experiments, including but not limited to liquid chromatographic separations, the mass spectrometer is underutilized during the time that is required for this chromatographic separation to occur. In many cases, methods to improve sample throughput are considered important for effective utilization of expensive instruments, and to reduce the time that is required to deliver information.
Two prior art approaches are considered. First, Waters/Micromass has proposed directing two independent streams of ions to one orifice of a mass spectrometer using a mechanical baffle in a system called LockSpray™. In this approach, two electrospray ionization (ESI) needles are brought to the vicinity of the ion orifice leading into the vacuum chamber. In order that the two sample streams not be mixed together as solutions, and delivered through one stream to one ESI needle, this system includes two ESI sources conveying separate sample streams to their respective needles. In order to keep the electrospray sources operational and to simplify data acquisition, the device includes a mechanical baffle driven by a motor. The mechanical device serves to allow only one, but not both sprays at a same time, to deliver ions towards the orifice leading into the mass spectrometer. Simultaneously, the alternate sprayer continues to operate, but the baffle prevents cross talk between the two sprays. One application, in LockSpray™, is to deliver a reference compound through one of the two spray needles. The reference compound is delivered to the mass spectrometer for short periods of time on an intermittent basis, to serve to re-calibrate the mass scale of the mass spectrometer. This ensures accurate mass measurements.
Covey et al. in U.S. application Ser. No. 10/148,888, filed on Dec. 14, 2000, propose a system including two or more ESI needles and having an electrode in the vicinity of each needle. By variation of the voltage to the deflector electrode of the ESI needle, the ions may either be moved toward the orifice of the mass spectrometer, or collide with the deflector (or other conductive surface) and not be delivered to the mass spectrometer.
In a second method, a commercial device is available that uses a mechanical multiport valve to deliver various liquid sample streams into one liquid stream, which is then delivered to an electrospray needle. In this case, the selection of liquid streams is performed before the electrospray ionization process. It is clear that liquid streams take time to be purged from the capillary leading to the electrospray needle, therefore the rate of switching is limited by this clean-out period. Faster switching of the liquid flows results in “memory” and “carry-over” from one stream to another. The mass spectrometer data is then of limited quality. Also, it is clear that the sample streams must be compatible, and must also have similar solvent composition and ionic strength.
The requirement for a mechanical, motor-driven device is a limitation of the prior art approaches. In addition to the reliability problems that are inherent in such mechanical systems, the delivery of ions from one or more of the sources is compromised relative to what it would be if the single ionizer were used in conjunction with the mass spectrometer. In the LockSpray™ system, the sensitivity of the sample stream is about 80% of what it would be in a conventional system because the ESI source cannot be located in an optimal position relative to the orifice of the mass spectrometer. In general, compared to mechanical devices, an electronic solution is less costly and more reliable. Although electronic manipulation of the ESI-produced ions by deflector electrode systems overcomes this limitation of mechanical devices, the deflector electrode approach also induces loss of sensitivity of each ESI source relative to what it would be if the ESI sources were located at optimum positions in front of the orifice leading into the mass spectrometer. It is an additional limitation of a deflector electrode system that the sensitivity of each ESI needle may not be equivalent to the other ESI needles, as a result of small variations in the mechanical positions relative to the orifice and to the deflector electrodes. The need for careful mechanical, electronic and gas flow adjustment limits the practical application of the multiple deflector approach to multiplexing ions from several ESI sources. Accordingly, this approach does not permit simultaneous parallel operation of two or more different types of sources. For example, simultaneous delivery of one sample with ESI and a second using atmospheric pressure MALDI is not practical.
Multiplexing switching of liquid sample flows prior to delivery of a single liquid stream to an ESI source (for example) using a multiport valve is slow and puts severe constraints on the types of liquid flows that may be sampled simultaneously. Liquid sample switching is practical if repeat identical analyses are being performed in parallel with identical conditions of flow and solvent media. Sample streams containing immiscible solvents cannot be mixed using a multiport valve system. High Performance Liquid Chromatography (HPLC) separations using solvent gradients are impractical unless the parallel separations have the same gradient, and are started simultaneously. In a liquid-multiplexing system, all samples are ionized with one type of source (ESI, Atmospheric Pressure Chemical Ionization (APCI), photoionization, thermospray, particle beam as some non-limiting examples) without opportunity to ionize in parallel using other types of ionization sources including atmospheric pressure Matrix Assisted Laser Desorption Ionization (MALDI) for example.